Data from our laboratory and others, have demonstrated that the plasma membrane redox system is, at least in part, responsible of the maintenance of the antioxidant capacity during oxidative stress challenges induced by the diet and aging. The upregulation of the plasma membrane redox system that occurs during CR decreases the levels of oxidative stress in aged membranes. CR extends life span of yeasts by decreasing NADH levels, which would connect this intervention to plasma membrane NADH-dependent dehydrogenases. CR modifies composition of fatty acid in the plasma membrane, resulting in decreased oxidative damage including lipid peroxidation. More importantly, plasma membrane redox activities and also the content of CoQ, which decline with age, are enhanced by CR providing protection to phospholipids and preventing the lipid peroxidation reaction progression. We are focusing our efforts on the generation of transgenic and knock out animals of the different dehydrogenases involved in this antioxidant system. We have successfully created NQO1 and Cyt-b5-reductase overexpressors and obtained NQO1 and NRF2 KO animals. We are setting longevity studies as well as short term interventions to fully characterize these new mouse lines. In collaboration with the laboratory of Dr. Placido Navas we have shown that the Saccharomyces cerevisiae homolog of Cyt-b5-reductase, NQR1, resides at the plasma membrane and when overexpressed extends both replicative and chronological lifespan. We demonstrated that NQR1 extends replicative lifespan in a SIR2-dependent manner by shifting cells towards respiratory metabolism and decreasing the pyridine nucleotide pool without altering the NAD+/NADH ratio. Chronological lifespan extension, in contrast, occurs via a SIR2-independent decrease in ethanol production. We conclude that NQR1 is a key mediator of lifespan extension by CR through its effects on yeast metabolism and discuss how these findings could suggest a function for this protein in lifespan extension in mammals.